Abstract: A breakdown in astrocyte-neuronal axis of communication is emerging as a common feature in a number of neurodegenerative diseases, including HIV-Associated Neurocognitive Disorder (HAND). Even in the combined antiretroviral therapy era, HAND affects approximately 50% of HIV infected individuals and its prevalence is expected to increase as the HIV-infected population ages. This underscores the need to better define cellular and molecular mechanisms driving HIV-mediated neuropathogenesis to devise novel strategies to prevent and/or treat HAND. We determined that the Wnt/ -catenin pathway is a restriction factor for productive HIV replication in astrocytes. Wnt/ -catenin regulates cell structure, synaptic activity, cell proliferation, and survival. The central mediator of this pathway ( -catenin) binds to TCF/LEF transcription factors and tethers on cognate genes to regulate their activity. We showed that -catenin restricts HIV by forming a complex with TCF-4 and SMAR-1 on the HIV LTR at site -143 from the +1 site to inhibit Pol II docking and consequently inhibits HIV transcription. These studies led to the first identification of functional TCF-4 binding sites on the HIV promoter and established their prevalence in 500 HIV isolates. Interestingly, inflammatory mediators such as IFN or HIV-1 Tat suppress -catenin activity while -catenin signaling inhibits the neuroinflammatory transcription factor CAAT/enhancer-binding proteins (C/EBP). We now provide evidence to suggest that disruption of Wnt/ -catenin in astrocytes negatively impact neurons. Specifically, we show that suppression of -catenin signaling in vitro and in vivo has a dramatic effect on the ability of astrocytes to scavenge for glutamate by inhibiting the expression of Excitatory Amino Acid Transporter 2 (EAAT-2/GLT-1 in rodents) and glutamine synthetase (GS). Excess glutamate is a common feature in neuroAIDS and other neurodegenerative diseases. Further, we show that higher plasma levels of Dickkopf- related protein 1 (DKK1, a soluble antagonist of Wnt signaling) are associated with worse global neurocognitive functioning among people living with HIV, suggesting that DKK1 may be a biomarker of HAND. These collective studies inform our central hypothesis which states that diminished -catenin signaling within astrocytes in response to an inflammatory mediator and/or HIV will perturb key functions of astrocytes and limit their neuroprotective properties. To test this hypothesis, we will determine the functional consequences of diminished Wnt/ -catenin signaling in astrocytes on neuronal injury in vitro and in vivo (Aim 1), assess the ability of activators of Wnt/ -catenin signaling to reduce and/or ameliorate HIV associated neuroinflammatory processes by inhibiting C/EBP leading to reduction in proinflammatory cytokines/chemokines, astrocyte activation and leukocyte infiltration (Aim 2), and determine whether molecules related to Wnt/ -catenin signaling are clinical and neuropathological biomarkers of HAND using well-defied samples from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) and California NeuroAIDS Tissue Network (CNTN) studies. Together, these studies will advance our understanding of the interplay between a neuroprotective pathway (Wnt/ -catenin) and the astrocyte/neuronal axis of communication and in doing so will have a broader applicability to neurodegenerative diseases to provide a path for translational studies.